Details of the Drug Combination

General Information of Drug Combination (ID: DCTMT54)

• Drug Combination Name: Ethambutol + Methylene blue
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Ethambutol (DMR87LC): Small molecular drug
  Methylene blue (DMJAPE7): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 2.79
  Bliss Independence Score: 2.79
  Loewe Additivity Score: 3.59
  LHighest Single Agent (HSA) Score: 3.59

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ethambutol

Disease Entry	ICD 11	Status	REF
Pulmonary tuberculosis	1B10.Z	Approved	[2]

Ethambutol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mycobacterium Arabinosyltransferase C (MycB embC)	TT1Q8GP	EMBC_MYCTU	Inhibitor	[5]

Ethambutol Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[6]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[6]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[6]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[6]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[7]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Secretion	[8]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[9]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[9]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[9]
Granzyme B (GZMB)	OTPPVIRS	GRAB_HUMAN	Increases Secretion	[8]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[9]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[9]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Increases Secretion	[8]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[9]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[7]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[9]

Indication(s) of Methylene blue

Disease Entry	ICD 11	Status	REF
Acquired methemoglobinemia	3A93	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]

Methylene blue Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	.	[10]
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[11]

Methylene blue Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Decreases Activity	[12]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[13]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Increases Expression	[14]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Activity	[15]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Decreases Activity	[16]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Activity	[15]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[17]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett. 1998 Feb 6;422(3):311-4.
• [4] ClinicalTrials.gov (NCT04370288) Clinical Application of Methylene Blue for Treatment of Covid-19 Patients. U.S. National Institutes of Health.
• [5] The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2009 Oct;53(10):4138-46.
• [6] Inhibition of cytochrome P450 by ethambutol in human liver microsomes. Toxicol Lett. 2014 Aug 17;229(1):33-40.
• [7] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [8] Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury. Chem Res Toxicol. 2016 Nov 21;29(11):1793-1795. doi: 10.1021/acs.chemrestox.6b00393. Epub 2016 Nov 9.
• [9] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [10] Photoluminescence of CdTe nanocrystals modulated by methylene blue and DNA. A label-free luminescent signaling nanohybrid platform. Phys Chem Chem Phys. 2009 Jul 7;11(25):5062-9.
• [11] Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1177-82.
• [12] Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Food Chem Toxicol. 2011 Aug;49(8):1773-81.
• [13] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [14] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [15] Defenses against oxidation in human erythrocytes: role of glutathione reductase in the activation of glucose decarboxylation by hemolytic drugs. J Lab Clin Med. 1991 Apr;117(4):325-31.
• [16] Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.